Genome-Wide Identification of Associations of Circulating Molecules with Spontaneous Coronary Artery Dissection and Aortic Aneurysm and Dissection

Circulating proteins play functional roles in various biological processes and disease pathogenesis. The aim of this study was to highlight circulating proteins associated with aortic aneurysm and dissection (AAD) and spontaneous coronary artery dissection (SCAD). We examined the associations of circulating molecule levels with SCAD by integrating data from a genome-wide association study (GWAS) of CanSCAD and 7 pQTL studies. Mendelian randomization (MR) analysis was applied to examine the associations between circulating molecule levels and AAD by using data from UK Biobank GWAS and pQTL studies. The SCAD-associated SNPs in 1q21.2 were strongly associated with circulating levels of extracellular matrix protein 1 (ECM1) and 25 other proteins (encoded by CTSS, CAT, CNDP1, KNG1, SLAMF7, TIE1, CXCL1, MBL2, ESD, CXCL16, CCL14, KCNE5, CST7, PSME1, GPC3, MAP2K4, SPOCK3, LRPPRC, CLEC4M, NOG, C1QTNF9, CX3CL1, SCP2D1, SERPINF2, and FN1). These proteins were enriched in biological processes such as regulation of peptidase activity and regulation of cellular protein metabolic processes. Proteins (FGF6, FGF9, HGF, BCL2L1, and VEGFA) involved in the Ras signaling pathway were identified to be related to AAD. In addition, SCAD- and AAD-associated SNPs were associated with cytokine and lipid levels. MR analysis showed that circulating ECM1, SPOCK3 and IL1b levels were associated with AAD. Circulating levels of low-density lipoprotein cholesterol and small very-low-density lipoprotein particles were strongly associated with AAD. The present study found associations between circulating proteins and lipids and SCAD and AAD. Circulating ECM1 and low-density lipoprotein cholesterol may play a role in the pathology of SCAD and AAD.